Abstract
The incidence of liver cancer, the second leading cause of cancer-related deaths has increased over the past few decades. Although recent treatments such as sorafenib are promising in patients with advanced hepatocellular carcinoma (HCC), the response rates remain poor thereby warranting the identification of novel therapeutic agents against liver cancer. Herein, we investigated the anti-cancer effect of ergosterol (a secondary metabolite in medicinal fungus) pretreatment followed by amphotericin B (AmB) treatment on liver cancer cell lines. We demonstrated that pretreatment with a nontoxic dose of ergosterol synergistically enhanced the cytotoxicity of AmB in both Hep3B and HepJ5 cells. The combination treatment-mediated suppression of cancer cell viability occurred through necrosis characterized by disrupted cell membrane and significant amounts of debris accumulation. In addition, we also observed a concomitant increase in reactive oxygen species (ROS) and LC3-II levels in HepJ5 cells treated with ergosterol and AmB. Our results suggest that ergosterol-AmB combination treatment effectively induced necrotic cell death in cancer cells, and deserves further evaluation for development as an anti-cancer agent.
Highlights
Liver cancer is the second leading cause of cancer-related deaths worldwide [1]
We demonstrated that pretreatment with a nontoxic dose of ergosterol synergistically enhanced the cytotoxicity of amphotericin B (AmB) in both Hep3B and HepJ5 cells
We demonstrated that combination treatment with ergosterol followed by AmB in a sequential manner led to a significant decrease in the viability of hepatocellular carcinoma (HCC) cells in a dosedependent manner
Summary
Liver cancer is the second leading cause of cancer-related deaths worldwide [1]. According to the epidemiological data in the United States, there is a substantial increase in HCC mortality and incidence in the past few decades [2]. Due to the shortage of liver donors and advanced tumor stage, or liver dysfunction, only a minority of HCC patients are eligible for curative treatments, including liver resection, transplantation, and local ablation [3]. While most intermediate cases are subjected to chemoembolization, advanced cases are mainly subjected to targeted therapies such as sorafenib treatment [4]. The response rates to these treatments remain poor, partly because HCC often accompanies liver cirrhosis, genetic heterogeneity, and cancer drug resistance [5,6,7].
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